title: Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity.
abstract: BACKGROUND
  Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance.
  
  
  OBJECTIVE
  We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome.
  
  
  METHODS
  In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data.
  
  
  RESULTS
  Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity.
  
  
  CONCLUSIONS
  Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome.
authors.affiliation: Department of Pediatrics, Anna Meyer University Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gambineri
authors.forename: Lucia
authors.initials: L
authors.lastname: Perroni
authors.forename: Laura
authors.initials: L
authors.lastname: Passerini
authors.forename: Lucia
authors.initials: L
authors.lastname: Bianchi
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Franco
authors.initials: F
authors.lastname: Meschi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bonfanti
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.forename: Alberto
authors.initials: A
authors.lastname: Tommasini
authors.forename: Anita
authors.initials: A
authors.lastname: Lawitschka
authors.forename: Anne
authors.initials: A
authors.lastname: Junker
authors.forename: Desiree
authors.initials: D
authors.lastname: Dunstheimer
authors.forename: Peter H
authors.initials: PH
authors.lastname: Heidemann
authors.forename: Giantonio
authors.initials: G
authors.lastname: Cazzola
authors.forename: Marco
authors.initials: M
authors.lastname: Cipolli
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Friedrich
authors.forename: Dragana
authors.initials: D
authors.lastname: Janic
authors.forename: Nadira
authors.initials: N
authors.lastname: Azzi
authors.forename: Erick
authors.initials: E
authors.lastname: Richmond
authors.forename: Silvia
authors.initials: S
authors.lastname: Vignola
authors.forename: Arrigo
authors.initials: A
authors.lastname: Barabino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiumello
authors.forename: Chiara
authors.initials: C
authors.lastname: Azzari
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D005838:Genotype; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D007410:Intestinal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D008297:Male; D009154:Mutation / Q000276:immunology; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D017434:Protein Structure, Tertiary / Q000235:genetics; D013577:Syndrome
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors